Production of useful substances through cell culture of plant, microbial, animal, and other cells has been employed in different industries, including brewing and manufacturing of food, chemical, and pharmaceutical products. For example, pharmaceutical products, including antibody drugs, comprise as a main component a substance produced by animal cells, and such substance can be produced by culturing animal cells and separating and purifying the target substance secreted into the culture solution.
Cell culture techniques are classified into batch culture, continuous culture (perfusion culture), and fed-batch culture (semi-batch culture). Batch culture is carried out by preparing a fresh medium each time, inoculating cells thereinto, and performing culture without adding another medium before harvesting. While quality of the product varies with each culture, the risk of contamination can be dispersed and reduced. Continuous culture is carried out by feeding media to a culture system at a constant speed and simultaneously removing the same amount of the culture solution therefrom. Using continuous culture, the culture environment can be easily maintained in a constant state, and productivity is stable. However, contamination disadvantageously continues if the culture environment is contaminated even once. Fed-batch culture is carried out by adding a medium or a particular component of the medium during culture without removing the culture product until culture is terminated. Fed-batch culture is carried out by regulating the cell density so as to optimize the proliferative properties, and diluting useful substances accumulated in the culture system, so as to maintain productivity.
Production of useful substances necessitates the use of large-size animal cell culture vessels exhibiting a high production yield. Sufficient aeration and agitation are required for large-size culture vessels in order to supply oxygen to be absorbed by cells and to remove carbon dioxide discharged by cells. However, shear stress applied through excessive agitation and bubble aeration damage cells, and such damage disadvantageously causes cell death. Accordingly, culture vessels are designed so as to minimize shear stress.
For example, JP 2006-296423 A describes a culture apparatus comprising a culture vessel, an agitation blade, and a drive control unit, and it discloses that the number of revolutions of the agitation blade is regulated, so as to prevent the cells from dying because of shear stress. Also, JP S61-149080 A (1986) discloses shear stress as a culture property that becomes uneven when the size of the apparatus is increased, and it also discloses a method for regulating shear stress. JP 2010-178734 A and JP2011-36189 A also disclose a technique for adequately designing the number of revolutions and the configuration of revolving blades in the culture vessel, as with JP 2006-296423 A, so as to reduce the shear stress applied to cells during culture, thereby avoiding cell death.